A Case of Pirfenidone-Induced Photosensitive Drug Eruption.

A 75-year-old male was diagnosed with idiopathic pulmonary fibrosis and treated with pirfenidone. He presented with an erythematous thick scaly patch on his face, neck, and both hands and arms. He had a history of significant exposure to sunlight without using sunscreen. All lesions were restricted to sun-exposed areas and appeared one month ago. Histopathological examination revealed necrotic keratinocytes, epidermal spongiosis, liquefaction degeneration of the basal layer, interface dermatitis, solar elastosis, and upper dermal perivascular lympho-histiocytic infiltration. Based on clinical and histopathological findings, the skin lesion could be diagnosed as photosensitive drug eruption induced by pirfenidone. Pirfenidone was discontinued for a month, and the patient was treated with oral and topical corticosteroids. Consequently, the skin lesion almost fully cleared, leaving mild postinflammatory hyperpigmentation. Although there are many reports of photosensitivity reactions to pirfenidone, dermatologists are still not familiar with this drug. Through this case presentation, clinicians should be aware of the potential phototoxic effects of pirfenidone and provide the necessary precautionary information to patients who take pirfenidone.

ERdj5 protects goblet cells from endoplasmic reticulum stress-mediated apoptosis under inflammatory conditions.

Endoplasmic reticulum stress is closely associated with the onset and progression of inflammatory bowel disease. ERdj5 is an endoplasmic reticulum-resident protein disulfide reductase that mediates the cleavage and degradation of misfolded proteins. Although ERdj5 expression is significantly higher in the colonic tissues of patients with inflammatory bowel disease than in healthy controls, its role in inflammatory bowel disease has not yet been reported. In the current study, we used ERdj5-knockout mice to investigate the potential roles of ERdj5 in inflammatory bowel disease. ERdj5 deficiency causes severe inflammation in mouse colitis models and weakens gut barrier function by increasing NF-κB-mediated inflammation. ERdj5 may not be indispensable for goblet cell function under steady-state conditions, but its deficiency induces goblet cell apoptosis under inflammatory conditions. Treatment of ERdj5-knockout mice with the chemical chaperone ursodeoxycholic acid ameliorated severe colitis by reducing endoplasmic reticulum stress. These findings highlight the important role of ERdj5 in preserving goblet cell viability and function by resolving endoplasmic reticulum stress.

Dysphagia with Unilateral Vocal Cord Paralysis in Herpes Zoster: A Case Report.

Herpes zoster is caused by the varicella-zoster virus, which becomes latent in ganglia after primary infection. When the varicella-zoster virus reactivates on the cranial nerve, the patient can suffer from cranial nerve palsy, pain, and skin lesions on the head and neck area. A 57-year-old immunocompetent male presented with dysphagia lasting 10 days. Computed tomography and other neurological findings were normal. However, laryngoscopy showed right vocal cord paralysis, which might be the reason for dysphagia in this patient. There was a grouped crusted lesion on the right posterior auricular area that appeared 5 days after the dysphagia. After famciclovir and prednisolone combination therapy, the patient was cured with no sequelae. This is a rare case of herpes zoster in an immunocompetent patient who presented with dysphagia. In addition, it was difficult to make an accurate diagnosis because his skin lesion appeared several days after dysphagia.

Amelioration of DSS-Induced Acute Colitis in Mice by Recombinant Monomeric Human Interleukin-22.

IL-22, a pleiotropic cytokine, is known to have a profound effect on the regeneration of damaged intestinal barriers. The tissue-protective properties of IL-22 are expected to be potentially exploited in the attenuation and treatment of colitis. However, because of the disease-promoting role of IL-22 in chronic inflammation, a comprehensive evaluation is required to translate IL-22 into the clinical domain. Here, we present the effective production of soluble human IL-22 in bacteria to prove whether recombinant IL-22 has the ability to ameliorate colitis and inflammation. IL-22 was expressed in the form of a biologically active monomer and non-functional oligomers. Monomeric IL-22 (mIL-22) was highly purified through a series of 3 separate chromatographic methods and an enzymatic reaction. We reveal that the resulting mIL-22 is correctly folded and is able to phosphorylate STAT3 in HT-29 cells. Subsequently, we demonstrate that mIL-22 enables the attenuation of dextran sodium sulfate-induced acute colitis in mice, as well as the suppression of pro-inflammatory cytokine production. Collectively, our results suggest that the recombinant mIL-22 is suitable to study the biological roles of endogenous IL-22 in immune responses and can be developed as a biological agent associated with inflammatory disorders.

The role of sonication in preparing injectable poly-l-lactic acid.

BACKGROUND: Injectable poly-l-lactic acid (PLLA) carries the risk of nodule or microlump formation. Various methods including sonication have been tried to minimize these adverse effects of PLLA. AIMS: This study investigated the change in size, distribution, and properties of PLLA particles after sonication, and the duration of sonication needed to reach the ideal particle size. METHODS AND MATERIALS: Two indicators, the average size of PLLA particles and diameter at 90%, were measured at each timepoint: at 0, 10, 60, 120, and 240 minutes of sonication. The characteristics and particle shape were assessed at 0 and 240 minutes. RESULTS: The average particle size and the diameter at 90% decreased drastically until 10 minutes of sonication and then increased slightly at 60 minutes. After 60 minutes, the average size and the diameter at 90% gradually decreased over time and reached 42.2 µm and 75.7 µm, respectively, at 120 minutes. After 240 minutes of sonication, the average particle size was 35.9 µm, much smaller than the smallest proper size required (40 µm). Standard deviation decreased gradually over time, which means that a more even distribution was obtained. Crystalline remnants were significantly less left with 120 minutes sonication compared to those with 120 minutes hydration only. PLLA particles were more cracked at the center, and microcrystals were more loosely distributed at the periphery after 120 minutes sonication. CONCLUSION: Sonication help reduce the average size of PLLA particles and achieve more even distribution. Therefore, we believe sonication may attribute to the safer use of PLLA.

Immunohistochemical Analysis of Differences of Toll-Like Receptor 2, Mast Cells, and Neurofilaments between Granulomatous Rosacea and Non-Granulomatous Rosacea.

BACKGROUND: Granulomatous rosacea is a distinct variant of rosacea because of its unique histopatholiogic findings. However, the pathogenesis of granulomatous rosacea has not yet been clearly demonstrated. AIMS AND OBJECTIVES: The aim of this study was to investigate the expression of toll-like receptor 2, mast cells, and neurofilaments in the granulomatous rosacea compared with the non-granulomatous rosacea. MATERIALS AND METHODS: Biopsy specimens were obtained from 12 patients with erythematotelangiectatic rosacea, 11 patients with granulomatous rosacea, and 11 control patients. Biopsy tissue blocks were subjected to immunohistochemical staining using antibodies against toll-like receptor 2, mast cells, and neurofilaments. RESULTS: In granulomatous rosacea, the expression of mast cells increased significantly, compared to the erythematotelangiectatic rosacea and the control group (P-value = 0.001 and 0.013, respectively). Additionally, the expression of toll-like receptor 2 in the granulomatous rosacea group was higher than that in the control group (P-value = 0.04). CONCLUSION: The results of this study suggest that the increased expression of mast cells may be a sign of chronic, later stage of granulomatous rosacea compared to the erythematotelangiectatic rosacea. The increased expression of toll-like receptor 2 suggests that cathelicidin-induced neuroimmune pathogenesis also contributes to the pathophysiology of granulomatous rosacea.

Crohn's Disease with Cutaneous Polyarteritis Nodosa in a Child: A Case Report.

A 10-year-old boy presented with a 1-day history of multiple painful erythematous skin lesions on his upper and lower extremities. He was admitted to the Department of Pediatrics with persistent right lower abdominal pain and diarrhea. Punch biopsy of a skin lesion on his lower leg showed necrotizing granulomatous vasculitis with septal panniculitis consistent with polyarteritis nodosa, and our differential diagnosis included cutaneous manifestations of Croh's disease. Abdominal ultrasonography revealed distended colonic loops suggestive of inflammatory bowel disease. Upper and lower gastrointestinal endoscopy revealed lesions involving the duodenum, cecum, colon, and rectum. He developed multiple perianal fistulas during hospitalization. Additional laboratory tests revealed positive results for anti-saccharomyces cerevisiae and antinuclear antibodies. Based on his clinical presentation and laboratory findings, he was diagnosed with Crohn's disease associated with cutaneous polyarteritis nodosa. We report a rare case of a child who presented with cutaneous polyarteritis nodosa as an extraintestinal manifestation of Crohn's disease.

A Rare Case of Cutaneous T-Cell Lymphoma Accompanied by Acute Monoblastic Leukemia and Diffuse Large B-Cell Lymphoma.

A 70-year-old female was referred for brown-to-gray colored papules and nodules on her lower legs. She had been diagnosed with diffuse large B-cell lymphoma (DLBCL) in her stomach, and myelodysplastic syndrome (MDS) by bone marrow biopsy. Three years after complete remission of DLBCL, she experienced DLBCL recurrence in her small bowel and was hospitalized. MDS had been stationary, but during the treatment of DLBCL, her laboratory findings suggested signs of leukemia. Bone marrow biopsy was done, and acute monoblastic leukemia (AMoL) was diagnosed. After 1 cycle of chemotherapy for AMoL, skin lesions developed, and her skin biopsy showed cutaneous T-cell lymphoma (CTCL). Terminal deoxynucleotidyl transferase staining and CD123 staining were negative, and bone marrow re-biopsy conducted after the skin lesion developed still showed monoblastic proliferation. Whether the CTCL represented with an AMoL lineage switch could not be completely proved due to the absence of molecular or clonal marker evaluations, but the possibility of coexistence of three different malignancies was higher. During treatment, a neutropenic fever developed, and the patient died due to sepsis. We herein report a rare case of CTCL accompanied by AmoL and DLBCL.

Morin Hydrate Inhibits Influenza Virus entry into Host Cells and Has Anti-inflammatory Effect in Influenza-infected Mice.

Influenza virus is the major cause of seasonal and pandemic flu. Currently, oseltamivir, a potent and selective inhibitor of neuraminidase of influenza A and B viruses, is the drug of choice for treating patients with influenza virus infection. However, recent emergence of oseltamivir-resistant influenza viruses has limited its efficacy. Morin hydrate (3,5,7,2',4'-pentahydroxyflavone) is a flavonoid isolated from Morus alba L. It has antioxidant, anti-inflammatory, neuroprotective, and anticancer effects partly by the inhibition of the NF-кB signaling pathway. However, its effects on influenza virus have not been studied. We evaluated the antiviral activity of morin hydrate against influenza A/Puerto Rico/8/1934 (A/PR/8; H1N1) and oseltamivir-resistant A/PR/8 influenza viruses in vitro. To determine its mode of action, we carried out time course experiments, and time of addition, hemolysis inhibition, and hemagglutination assays. The effects of the co-administration of morin hydrate and oseltamivir were assessed using the murine model of A/PR/8 infection. We found that morin hydrate reduced hemagglutination by A/PR/8 in vitro. It alleviated the symptoms of A/PR/8-infection, and reduced the levels of pro-inflammatory cytokines and chemokines, such as TNF-α and CCL2, in infected mice. Co-administration of morin hydrate and oseltamivir phosphate reduced the virus titers and attenuated pulmonary inflammation. Our results suggest that morin hydrate exhibits antiviral activity by inhibiting the entry of the virus.

Plasmacytoid dendritic cells regulate colitis-associated tumorigenesis by controlling myeloid-derived suppressor cell infiltration.

Toll-like receptor (TLR)3 and TLR7 are important for stimulating plasmacytoid dendritic cells (pDCs), which secrete type I interferon. Mice deficient for TLR3 and TLR7 (TLR3-/-TLR7-/-) reportedly exhibit deteriorated colitis because of impaired pDCs. However, the role of pDCs in tumorigenesis-associated inflammation progression has not been studied. We treated wild-type or TLR3-/-TLR7-/- mice with dextran sulfate sodium (DSS) and/or azoxymethane (AOM) and examined colon mucosa, measured body weight and colon length of mice, and examined pDC and myeloid-derived suppressor cell (MDSC) accumulation. Further, we depleted pDCs in AOM/DSS-treated wild-type mice by treating them with anti-PDCA-1 antibodies. We found that MDSCs significantly increased, while pDCs decreased in TLR3-/-TLR7-/- mice. Moreover, TLR3-/-TLR7-/- mice developed colitis-associated colon cancer following AOM/DSS treatment. Additionally, we showed that a defect in TLR7 of pDCs is responsible for the aggravation of colitis-associated colon cancer. Further, we showed that TLR7 ligand mitigates colitis-associated colon cancer. Collectively, our results demonstrate that gut pDCs play a crucial role in reducing colorectal cancer development via the regulation of infiltrating MDSCs.

KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth.

Anaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPM-ALK-positive ALCL cells. Additionally, it induced G0/G1 cell cycle arrest and apoptosis by blocking downstream signals including STAT3, Akt, and ERK1/2. Tumor growth was strongly suppressed in mice inoculated with Karpas-299 tumor xenografts and orally treated with KRCA-0008 (50 mg/kg, BID) for 2 weeks. Our results suggest that KRCA-0008 will be useful in further investigations of ALK signaling, and may provide therapeutic opportunities for NPM-ALK-positive ALCL patients.

A Case of Solitary Fibrous Tumor of Subungual Region.

Solitary fibrous tumor (SFT) is a relatively uncommon mesenchymal neoplasm that usually arises in the pleura, but also has been reported in numerous extrapleural locations, including cutaneous site. The skin lesion presents as a circumscribed nodule or tumor, mainly on the head and neck. A 41-year-old male presented with 6 months history of nail lesion without symptom on the left third finger. The lesion is slightly yellowish discoloration with subungual erythematous nodule and distal onycholysis. Biopsy specimen from the nail lesion showed the spindle cells form patternless pattern with hypercellular and hypocellular area. And small blood vessels and dilated vascular spaces were present. The result of special stain for specimen showed that positive for CD34, Bcl-2, and CD99 but negative for S-100, FactorXIIIa, and smooth muscle action. Recognition of this uncommon location of SFT is important because of possible confusion with other subungual tumors, including glomus tumor, fibroma and other fibrohistiocytic tumors like dermatofibrosarcoma protuberans, superficial acral fibromyxoma and cellular digital fibroma. Here in, we report a case of SFT of subungual region. We think this case is interesting because of uncommon location and may be helpful to more understand the character of this disease.

A Case of Generalized Lichen Sclerosus et Atrophicus.

A 62-year-old female, with previous history of asthma and hypertension, presented with generalized hyperpigmented skin lesion, found a year ago. Physical examination revealed brown colored lichenified and sclerotic patches on the lower abdomen and flexural areas of extremities. Punch biopsy was performed and histopathological examination revealed hyperkeratosis, follicular plugging and thinning in epidermis. In dermoepidermal junction, cleft like space separating atrophic epidermis and dermis was seen. Also, lichenoid lymphocytic infiltration was observed in mid-dermis. Based on clinical and histopathological findings, a diagnosis of generlaized lichen sclerosus et atrophicus (LSA) was made. Other laboratory examinations were unremarkable. As there is no standard treatment for LSA, the patient received various treatments including topical steroid, tacrolimus and narrow-band ultraviolet B therapy. The skin lesion has softened and its color improved after treatment. LSA is defined as infrequent chronic inflammatory dermatosis with anogenital and extragenital manifestations. Generalized type is rare and genital involvement is the most frequent and often the only site of involvement. We report this case as it is an uncommon type of LSA with generalized hyperpigmented and sclerotic skin lesion in a postmenopausal female patient.

Clinicopathological differentiation between Pityrosporum folliculitis and acneiform eruption.

Distinguishing between Malassezia folliculitis (Pityrosporum folliculitis [P. folliculitis]) and acneiform eruption, based on clinicopathological features, is challenging for clinicians. In the literature, the histopathological differences between P. folliculitis and acneiform eruption lesions have been poorly described. We aimed to determine the clinicopathologic distinctions between P. folliculitis and acneiform eruption by retrospectively analyzing the histology of hematoxylin and eosin stained tissue sections obtained from 52 patients diagnosed with these lesions. The presence of fungal spores in the follicular lumen was most consistent with a P. folliculitis diagnosis (P < 0.001). However, intrafollicular inflammation (P = 0.009), irregular patterns of keratin plugging (P = 0.008), and nuclear dust in the follicular lumen (P < 0.001) favored an acneiform eruption diagnosis. These intrafollicular characteristics and inflammatory differences are believed to be caused by necrotic keratinocytes that lead to vacuolar changes in the follicular wall (P = 0.013). We did not observe any difference between P. folliculitis and acneiform eruption lesions in terms of perifollicular inflammatory cell infiltration. Our study demonstrated that significant differences exist between P. folliculitis and acneiform eruption lesions relative to the presence of necrotic keratinocytes in the follicular wall, intrafollicular characteristics, and inflammatory cell infiltrations. Necrotic keratinocytes are believed to have a key role in these differences. These findings may contribute to an improved understanding of the pathogenesis and differential diagnosis of P. folliculitis and acneiform eruption.

Esterase-sensitive cleavable histone deacetylase inhibitor-coupled hyaluronic acid nanoparticles for boosting anticancer activities against lung adenocarcinoma.

4-Phenylbutyric acid (PBA)-installed hyaluronic acid (HA)-based nanoparticles (NPs) were developed for amplifying the anticancer potential of curcumin (CUR) for lung cancer therapy. PBA was introduced to the HA backbone as a hydrophobic segment of a nanoassembled structure and as a histone deacetylase (HDAC) inhibitor for cancer therapy. PBA was released from the HA-PBA conjugate (HAPBA) via an esterase-responsive cleavage of ester bonds in cancer cells and may affect the dissociation of NP structure. CUR-entrapped HAPBA-based NPs, with 265 nm hydrodynamic size, unimodal size distribution, negative zeta potential, and sustained drug release, were fabricated. Co-treatment of A549 cells by PBA and CUR elevated the antiproliferation efficiency compared with CUR-treatment. CUR-loaded HAPBA NPs also exhibited a significantly lower IC50 value compared with the CUR and HAPBA10 + CUR groups (p < 0.05). Cy5.5-labeled HAPBA NPs containing CUR group displayed higher accumulation in tumor tissue and less distribution in liver and spleen after intravenous injection compared with the Cy5.5-injected group in A549 tumor-bearing mouse model. Multiple dosing of CUR-loaded HAPBA NPs in A549 tumor-bearing mouse model exhibited efficient tumor growth suppression and apoptosis-inducing effects. CD44 receptor targeting and HDAC inhibiting HAPBA NPs can be used to boost the anticancer potentials of drug cargo for the therapy of CD44 receptor-expressed cancers.

Manassantin B shows antiviral activity against coxsackievirus B3 infection by activation of the STING/TBK-1/IRF3 signalling pathway.

Coxsackievirus B3 (CVB3) is an important human pathogen associated with the development of acute pancreatitis, myocarditis, and type 1 diabetes. Currently, no vaccines or antiviral therapeutics are approved for the prevention and treatment of CVB3 infection. We found that Saururus chinensis Baill extract showed critical antiviral activity against CVB3 infection in vitro. Further, manassantin B inhibited replication of CVB3 and suppressed CVB3 VP1 protein expression in vitro. Additionally, oral administration of manassantin B in mice attenuated CVB3 infection-associated symptoms by reducing systemic production of inflammatory cytokines and chemokines including TNF-α, IL-6, IFN-γ, CCL2, and CXCL-1. We found that the antiviral activity of manassantin B is associated with increased levels of mitochondrial ROS (mROS). Inhibition of mROS generation attenuated the antiviral activity of manassantin B in vitro. Interestingly, we found that manassantin B also induced cytosolic release of mitochondrial DNA based on cytochrome C oxidase DNA levels. We further confirmed that STING and IRF-3 expression and STING and TBK-1 phosphorylation were increased by manassantin B treatment in CVB3-infected cells. Collectively, these results suggest that manassantin B exerts antiviral activity against CVB3 through activation of the STING/TKB-1/IRF3 antiviral pathway and increased production of mROS.

BIG2-ARF1-RhoA-mDia1 Signaling Regulates Dendritic Golgi Polarization in Hippocampal Neurons.

Proper dendrite development is essential for establishing neural circuitry, and Rho GTPases play key regulatory roles in this process. From mouse brain lysates, we identified Brefeldin A-inhibited guanine exchange factor 2 (BIG2) as a novel Rho GTPase regulatory protein involved in dendrite growth and maintenance. BIG2 was highly expressed during early development, and knockdown of the ARFGEF2 gene encoding BIG2 significantly reduced total dendrite length and the number of branches. Expression of the constitutively active ADP-ribosylation factor 1 ARF1 Q71L rescued the defective dendrite morphogenesis of ARFGEF2-null neurons, indicating that BIG2 controls dendrite growth and maintenance by activating ARF1. Moreover, BIG2 co-localizes with the Golgi apparatus and is required for Golgi deployment into major dendrites in cultured hippocampal neurons. Simultaneous overexpression of BIG2 and ARF1 activated RhoA, and treatment with the RhoA activator lysophosphatidic acid in neurons lacking BIG2 or ARF1 increased the number of cells with dendritic Golgi, suggesting that BIG2 and ARF1 activate RhoA to promote dendritic Golgi polarization. mDia1 was identified as a downstream effector of BIG2-ARF1-RhoA axis, mediating Golgi polarization and dendritic morphogenesis. Furthermore, in utero electroporation of ARFGEF2 shRNA into the embryonic mouse brain confirmed an in vivo role of BIG2 for Golgi deployment into the apical dendrite. Taken together, our results suggest that BIG2-ARF1-RhoA-mDia1 signaling regulates dendritic Golgi polarization and dendrite growth and maintenance in hippocampal neurons.

Trans-scirpusin A showed antitumor effects via autophagy activation and apoptosis induction of colorectal cancer cells.

Trans-Scirpusin A (TSA) is a resveratrol oligomer found in Borassus flabellifer L. We found that TSA inhibited the growth of colorectal cancer Her2/CT26 cells in vivo in mice. Although some cytotoxic T lymphocytes (CTLs) were induced against the tumor-associated antigen Her2, TSA treatment did not significantly increase the level of Her2-specific CTL response compared to that with vehicle treatment. However, there was a significant increase in the level of TNF-α mRNA in tumor tissue and Her2-specific Ab (antibody) production. More importantly, we found that TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25+FoxP3+ regulatory T cells and myeloid-derived suppressor cells (MDSCs). We detected the induction of autophagy in TSA-treated Her2/CT26 cells, based on the increased level of the mammalian autophagy protein LC3 puncta, and increased conversion of LC3-I to LC3-II. Further, TSA induced 5' AMP-activated protein kinase (p-AMPK) (T172) and inhibited mammalian target of rapamycin complex 1 (mTORC1) activity as estimated by phosphorylated ribosomal protein S6 kinase beta-1 (p-p70S6K) levels, thereby suggesting that TSA-mediated AMPK activation and inhibition of mTORC1 pathway might be associated with autophagy induction. TSA also induced apoptosis of Her2/CT26 cells, as inferred by the increased sub-G1 mitotic phases in these cells, Annexin V/PI-double positive results, and TUNEL-positive cells. Finally, we found that the combined treatment of mice with docetaxel and TSA successfully inhibited tumor growth to a greater extent than docetaxel alone. Therefore, we propose the use of TSA for supplementary anticancer therapy to support anti-neoplastic drugs, such as docetaxel, by inducing apoptosis in cancer cells and resulting in the induction of neighborhood anti-cancer immunity.

Boronic acid-tethered amphiphilic hyaluronic acid derivative-based nanoassemblies for tumor targeting and penetration.

(3-Aminomethylphenyl)boronic acid (AMPB)-installed hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated for tumor-targeted delivery. The amine group of AMPB was conjugated to the carboxylic acid group of hyaluronic acid (HA) via amide bond formation, and synthesis was confirmed by spectroscopic methods. HACE-AMPB/MB NPs with a 239-nm mean diameter, narrow size distribution, negative zeta potential, and >90% drug encapsulation efficiency were fabricated. Exposed AMPB in the outer surface of HACE-AMPB NPs (in the aqueous environment) may react with sialic acid of cancer cells. The improved cellular accumulation efficiency, in vitro antitumor efficacy, and tumor penetration efficiency of HACE-AMPB/MB NPs, compared with HACE/MB NPs, in MDA-MB-231 cells (CD44 receptor-positive human breast adenocarcinoma cells) may be based on the CD44 receptor-mediated endocytosis and phenylboronic acid-sialic acid interaction. Enhanced in vivo tumor targetability, infiltration efficiency, and antitumor efficacies of HACE-AMPB NPs, compared with HACE NPs, were observed in a MDA-MB-231 tumor-xenografted mouse model. In addition to passive tumor targeting (based on an enhanced permeability and retention effect) and active tumor targeting (interaction between HA and CD44 receptor), the phenylboronic acid-sialic acid interaction can play important roles in augmented tumor targeting and penetration of HACE-AMPB NPs. STATEMENT OF SIGNIFICANCE: (3-Aminomethylphenyl)boronic acid (AMPB)-tethered hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated and their tumor targeting and penetration efficiencies were assessed in MDA-MB-231 (CD44 receptor-positive human adenocarcinoma) tumor models. MB, which exhibited antitumor efficacies via the inhibition of angiogenesis and hypoxia inducible factor (HIF)-1, was entrapped in HACE-AMPB NPs in this study. Phenylboronic acid located in the outer surface of HACE-AMPB/MB NPs (in the aqueous milieu) may react with the sialic acid over-expressed in cancer cells and intramolecular B‒O bond can be formed. This phenylboronic acid-sialic acid interaction may provide additional tumor targeting and penetration potentials together with an enhanced permeability and retention (EPR) effect (passive tumor targeting) and HA-CD44 receptor interaction (active tumor targeting). Developed HACE-AMPB NP may be one of promising nanocarriers for the imaging and therapy of CD44 receptor-expressed cancers.